During ischaemic processes related to acute myocardial infarction or angina pectoris, a lipid accumulation in the myocardium is produced. This fact has not only been observed in test animals (Straeter-Knowlen I M et al, Circulation 1996; Chabowski A et al, FEBS Lett 2006) but also in patients (Golfbarb J W et al, Radiology 2009). Furthermore, there is also experimental evidence showing that dyslipidemia contributes to the exacerbation of cardiac alterations induced by ischaemia in animal models (Osipov R M et al, Circulation 2009; Kim E et al, J Neurosci 2008). It has recently been demonstrated that high doses of VLDL alter calcium (Ca2+) regulation in cardiomyocytes and that these alterations induced by VLDL are exacerbated in situations of hypoxia, with SERCA-2 sarcoplasmic reticulum protein playing a crucial role (Castellano J et al, J Mol Cell Cardiol 2011).
Ischaemia as a basis of heart failure results in the condition known as ischaemic cardiomyopathy. Ischaemic cardiomyopathy is with high frequency a result of coronary disease, whose underlying pathology is atherosclerosis (Gersh B J et al, journal 1997). Atherosclerotic plaque evolution produces a progressive imbalance between oxygen supply and demand in the myocardium. The gravest outcome of the atherosclerotic process, infarction, is in 80% of cases due to atherosclerotic plaque rupture, the formation of the thrombus, and the total or partial occlusion of the vessel (Burke A P et al, Med Clin North America 2007). Dyslipidemia is a key risk factor in ischaemic cardiomyopathy generation, mainly because of its role at the beginning and in the development of atherosclerosis. In situations of dyslipidemia there is an increase in the influx of lipoproteins towards the arterial intimae, where they are modified by means of oxidation and aggregation through interaction with the proteoglycanes that make up the extracellular matrix (Sartipy P et al, Circ Res 2000; Hakala J K et al, ATVB 2001). Modified lipoprotein uptake by smooth muscular cells from the vascular wall and macrophages leads to the formation of foam cells in the vascular wall. Low-density lipoprotein receptor-related protein (LRP1) has been identified as a key receptor for uptake of LDL modified by intracellular cholesterol aggregation and accumulation in smooth muscle cells from the vascular wall and macrophages as well as for their transformation into foam cells (Llorente-Cortés V et al, ATVB 2000; Llorente-Cortés et al, ATVB 2002; Llorente-Cortés et al, J Lipid Res 2007, Llorente-Cortés et al, Cardiovasc Res 2007). LRP1 is upregulated in advanced atherosclerotic lesions rich in lipids (Luoma J et al, J Clin Invest 1994; Llorente-Cortés et al, Eur J Clin Invest 2004) and may be considered as a heart disease biomarker as there are clinical trials showing the relationship between LRP1 expression alteration and coronary disease (Handschug K et al, J Mol Med 1998; Schulz et al, Int J Cardiol 2003). It has also been shown that risk factors relevant for atherosclerosis development such as hypercholesterolemia and hypertension upwards regulate LRP1 expression in the vascular wall (Llorente-Cortés et al, Circulation 2002; Sendra J et al, Cardiovasc Res 2008). It has later been shown that aggregated LDL uptake by LRP1 regulates the expression and activation of the tissue factor, a main coagulation activator, therefore regulating thrombus formation by means of a RhoA and sphyngomyelin-dependant mechanism (Llorente-Cortés et al, Circulation 2004; Camino-López S et al, Cardiovasc Res 2007; Camino-López S et al, J Thromb Haemost 2009). In addition to all these processes it has been described how LRP1 takes part in the regulation of extracellular matrix composition (Strickland D K et al, Trends Endocrinol Metab 2002), may promote receptor internalization (Wu L et al, J Cell Biochem, 2005) and regulates the activity of various intracellular signaling proteins (Herz J et al, J Clin Invest 2001).
The role of LRP1 in cardiomyocytes and the consequences of alterations in its expression for lipid metabolism are wholly unknown at this time. It is known that lipase lipoprotein present in the surface of cardiomyocytes mediates LDL uptake. Nonetheless, lipase lipoprotein uses a receptor so far unidentified for the selective uptake of cholesterol, and it is not the classic LDL receptor (Yagyu H et al, J Clin Invest 2003; Yokoyama M et al, J Lipid Res 2007). It has also been demonstrated that LRP1 mediates selective cholesterol uptake in vascular cells (Llorente-Cortés et al, ATVB 2006).
Cardiomyocytes accumulate lipids in different pathophysiological conditions, of which processes of acute ischaemia are one (Chabowski A et al, FEBS Lett 2006; Goldfarb J W et al, Radiology 2009), though the mechanisms by which this occurs are to a large extent unknown. One of the mechanisms participating in triglyceride (TG) accumulation in ischaemic situations is the increase of endogenous TG synthesis due to hypoxia (Boström P et al, ATVB 2006). Nonetheless, cardiomyocytes may catch lipids from lipoproteins rich in TG such as VLDL and chylomicrons. It is known that CD36 and lipase lipoprotein participate in the uptake of VLDL fatty acids by cardiomyocytes (Bharadwaj K G et al, J Biol Chem 2010). As CD36 is increased in situations of hypoxia (Mwaikambo B R et al, J Biol Chem 2009), it is plausible that increased CD36 levels participate in the accumulation of TG observed in the ischaemic heart. Although it is known that the heart may take up cholesterol from VLDL (Bharadawaj K G et al, J Biol Chem 2010) and chylomicrons (Fielding C J et al, J Clin Invest 1978), the mechanisms involved in the entry of cholesterol into the heart are completely unknown.
Ischaemia is associated with an electromechanical dysfunction and with severe alterations in intracellular calcium dynamics (García-Dorado D et al, Cardiovasc Res 2006; Takukder M A et al, Cardiovasc Res 2009), key for cardiac functionality. Moreover, it recently has been demonstrated that cardiomyocytes exposed to high doses of VLDL suffer from intracellular lipid accumulation, a decrease in SERCA-2 expression, calcium amplitude and sarcoplasmic reticulum calcium content. These effects were exacerbated by exposing the cultivated myocytes to a hypoxic environment. The results highlight the central role of SERCA-2 in the empowerment by hypoxia of alterations in calcium handling induced by VLDL (Castellano J et al, JMCC 2011). It has also recently been described how LRP1 is upregulated by hypoxia in smooth muscular cells from the vascular wall (Castellano J et al, ATVB 2011). These data demonstrate the importance of understanding the molecular mechanisms involved in lipid uptake by cardiomyocytes in ischaemic situations and the importance of knowing the role of LRP1 in this process.
Therefore, there is currently a need to develop a method for modulating lipoprotein receptors such as LRP1 to treat and prevent the accumulation of neutral lipids such as cholesteryl ester (CE) in cardiomyocytes during ischaemic events, which would minimize the cardiac alterations of acute myocardial infarction or angina pectoris, induced by dyslipidemia or other conditions that accompany ischaemia.